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UW Scientists Have Developed New Optogenetic Tools for Biomedical Research

January 24, 2011 — Researchers at the University
of Wyoming have characterized and engineered new proteins that expand the use
of light as a tool to manipulate cell cultures, tissues and laboratory model
animals.

In a paper published in the
Journal of Biological Chemistry, UW researchers Min-Hyung Ryu, Oleg Moskvin,
Jessica Siltberg-Liberles and Mark Gomelsky describe novel light-activated
proteins to study cellular regulatory networks. They say this technology,
called optogenetics, is beginning to revolutionize biomedical research. Optogenetic
approaches have already been applied to investigating neural circuits relevant
to locomotion and awakening, as well as to brain disorders such as Parkinson's
disease, schizophrenia and epilepsy.

Animals have very few
proteins that are naturally sensitive to light, says Siltberg-Liberles,
director of the INBRE (IDeA Networks of Biomedical Research Excellence) Bioinformatics
service core. She says optogenetics allows one to "borrow" natural
light-activated proteins from microbes or plants and deliver their genes into
model animal organisms.

"We are used to
regulating cellular processes with drugs. However, it is difficult, if not
impossible, to deliver drugs to specific cells and organs that need to be
treated while sparing the rest of the organism from the unwanted side
effects," says Gomelsky, an associate professor in the UW Department of
Molecular Biology.

"Then, once a drug is
administered, it takes time for it to act and to be removed from an organism,
so we have relatively little control over timing," Gomelsky adds. "The beauty
of optogenetic approaches is that light can be delivered by lasers with
extremely high spatial precision; therefore, one can manipulate only target
cells. Furthermore, turning light on and off takes a split second, so one gains
high temporal precision as well."

"It would be even more
powerful if we could design proteins that have desired functions to be turned
on by light of a specific waveband," Siltberg-Liberles says. "However, at
present, designing light-activated proteins is only half-science and half-art."

There is a high demand for
developing better light switches and a new set of functions that can be
controlled by light, says Siltberg-Liberles. She explains that two molecules,
cAMP and cGMP, control a variety of cellular processes, such as cell growth,
blood glucose levels, cardiac function, learning, memory, cancer cell survival
and others. These two molecules are synthesized by the enzymes called adenylyl
and guanylyl cyclases. The UW team worked on making the light-activated
versions of these cyclases.

"We have identified a
Blue-Light activated Adenylyl Cyclase, BlaC, in a genome of the marine
bacterium Beggiatoa. After characterizing the protein, we found that it is
better controlled by light than any protein of that function known to date,"
she says. "Using computational and protein engineering approaches, we
redesigned BlaC to function as a light-activated guanylyl cyclase, a new
activity that has never previously existed."

Siltberg-Liberles says as
soon as the paper appeared in the online early version of Journal of Biological
Chemistry, the researchers started receiving requests by research groups in the
United States and Europe that wanted to use the light-activated cyclases to
study diverse processes in various animal systems.

"Our paper has been
recommended by a Faculty of 1000 Biology, a group of top experts that highlights
noteworthy research findings," she says.

Research on light-activated
proteins continues. UW scientists are now engineering infrared-light activated
cyclases, which Gomelsky says will be important for biomedical research because
infrared light penetrates animal tissues much deeper than blue light.

"We are grateful to
INBRE for partial support of our light-activated protein engineering project and
also for creating the Bioinformatics service core. Without access to Jessica's
expertise, this project would not have been possible," says Gomelsky.

Jun Ren, INBRE director, says
the Bioinformatics service core was established to add computational resource
and expertise in bioinformatics to experimental life scientists across campus
and this is a good example of what it can do. Siltberg-Liberles adds that the
Bioinformatics service core is available for all life scientists and new
projects are always welcome.

Funded with a five-year grant
from the National Institutes of Health, INBRE focuses on diseases such as
cardiovascular problem, diabetes and obesity that are among the leading causes
of death and high health care costs in the United States and that are
significant health issues in Wyoming.

Photo:Min-Hyung Ryu, a Ph.D.
student in the University of Wyoming Department of Molecular Biology, examines
an image of bacteria growing on a Petri dish. He is first author of a UW paper
published in the Journal of Biological Chemistry.